Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum...

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Endothelin receptor A (ET_A) is a tumor antigen implicated in cancer progression and metastasis.
• Existing ET_A antagonists are small molecules; antibody-based therapies require optimization.
• Previous work identified the anti-ET_A antibody AG8 with anticancer effects but suboptimal properties.

Purpose of the Study:

• To engineer an improved anti-ET_A antibody with enhanced therapeutic potential.
• To optimize antibody binding affinity, thermostability, and serum half-life.
• To evaluate the in vivo antitumor efficacy of the engineered antibody.

Main Methods:

• Framework region engineering of the AG8 antibody to create MJF1.
• Introduction of an Fc variant (PFc29) to MJF1, creating MJF1-PFc29.
• Assessment of ET_A binding affinity, thermostability, serum half-life in FcRn transgenic mice, and in vivo antitumor activity in colorectal cancer xenografts.

Main Results:

• Engineered antibody MJF1 showed improved thermostability and ET_A binding affinity.
• Fc-engineered MJF1-PFc29 exhibited a 4.2-fold increase in serum half-life.
• MJF1-PFc29 demonstrated superior tumor growth inhibition in colorectal cancer models compared to MJF1.

Conclusions:

• Engineered anti-ET_A antibody MJF1-PFc29 possesses enhanced biochemical properties and potent antitumor activity.
• MJF1-PFc29 shows significant therapeutic potential for treating ET_A-expressing cancers, including colorectal cancer.
• This study highlights the successful engineering of antibodies for improved cancer therapy.